The metabolic syndrome of aging represents a constellation of metabolic defects that are important risk factors for age-related disease and is the focus of this Program Project. Components of this syndrome, including dyslipidemia, hypertension and impaired fibrinolysis are associated with increased risk of atherosclerosis and thrombosis. A pro-inflammatory state with increased plasma levels of cytokines and acute phase reactants may also be implicated in the increased cardiovascular disease (CVD) risk. This syndrome is commonly associated with the development of type 2 diabetes, which affects almost 30% of individuals over age 70. Diabetes in the elderly is characterized by a high frequency of isolated post-challenge hyperglycemia (IPH) and hyperlipidemia and is often undiagnosed. Elderly subjects with isolated post-challenge hyperglycemia have a relative risk of 1.5-3.0 for CVD and total mortality, an effect that appears to be independent of other established CVD risk factors. In this Project we propose to demonstrate that these markers will be elevated in elderly subjects because of increased postprandial levels of glucose and free fatty acids. Our hypothesis is that postprandial hyperglycemia (PPH), which is characteristic of aging individuals, promotes CVD by inducing expression of several peptides that have roles in thrombosis and inflammation and which are transcriptionally induced by nutrients in fat and other tissues. Furthermore, PPH may induce oxidant stress and lead to impaired endothelial cell function. We aim to define these vascular risk markers in elderly subjects with PPH (n=40), compared with age-matched normoglycemic controls (n=40). We will then test in an 18 week cross-over study whether treatment of PPH in the elderly will decrease biological markers for CVD and improve endothelial function. Positive results will support early treatment of this growing elderly population with postprandial hyperglycemia. We plan this as a pilot study to test safety, efficacy and adherence in this population so that a larger study can be planned with clinically relevant endpoints, including CVD events and mortality. This proposal will serve as one of the translational human research components of the Program Project, implicating nutrient excess in the increase of CVD seen with aging.